Skip to main content
Premium Trial:

Request an Annual Quote

Alzheimer's Disease Risk Linked to Noncoding Variants in APOE Region

NEW YORK – Noncoding variants within the APOE region may contribute to risk of developing Alzheimer's disease, a new analysis has found.

The link between mutations in the apolipoprotein E gene and Alzheimer's disease risk has been known for more than 25 years. But it has been unclear to what degree genetic heterogeneity at the APOE locus contributes to disease risk independently of the APOE ε2, ε3, and ε4 genotypes. Some previous studies have suggested that two noncoding SNVs, one in TOMM40 and one in APOC1, might also be associated with disease risk or disease-related traits.

Through a genetic association study of nearly 19,000 individuals, researchers from the Alzheimer's Disease Genetics Consortium found associations between variant rs2075650 in the TOMM40 gene and Alzheimer's disease risk among ε4 homozygotes, and between two novel variants and disease risk.

"The results of this genetic association study suggest that ε2/ε3/ε4 alleles are not the only variants in the APOE region that are associated with AD risk," senior author Chang-En Yu from the University of Washington and his colleagues wrote in their paper, which appeared in JAMA Network Open on Thursday

For their analysis, the researchers used Alzheimer's Disease Genetics Consortium data on 18,795 individuals of European ancestry, about half of whom had Alzheimer's disease.

The APOE ε2 allele was present among 3.5 percent of cases and 8 percent of controls, while the APOE ε4 allele was present among 37.9 percent of cases and 13.7 percent of controls. Their cohort further included 71 ε2 homozygotes, 8,848 ε3 homozygotes, and 1,503 ε4 homozygotes. 

The researchers used four logistic mixed models that took sex, cohort, population structure, and relatedness into account to examine whether more than 14,400 variants in the APOE gene region were associated with disease risk. The first model had no APOE adjustments, while the second adjusted for the number of ε2 and ε4 alleles. The third model and fourth models, meanwhile, were restricted to ε3 homozygotes and ε4 homozygotes, respectively.

Using the first model, they uncovered associations between rs2075650 in the TOMM40 gene and Alzheimer's disease as well as between rs4420638 near APOC1 and the disease. Rs2075650 remained nominally associated with Alzheimer's disease among ε4 homozygotes, but adjusting for APOE eliminated the link between rs4420638 and the disease.

The TOMM40 SNV is located in an intron and is predicted to alter a handful of transcription factor binding site motifs. It is further associated with the expression levels of TOMM40, PVRL2, and HIF3A.

Beyond TOMM40 and APOC1, the researchers uncovered links between other variants in the region and Alzheimer's disease risk. For instance, there was a significant association between rs192879175 and AD in ε3 homozygotes and a nominal one between rs143764218 and AD after APOE adjustment and in ε3 homozygotes.

Both rs192879175 and rs143764218 are rare variants with minor allele frequencies of 0.01 and 0.05, respectively, in Europeans and neither has been linked previously to Alzheimer's disease or any other trait through a genome-wide association study. Both also fall between genes but exhibit characteristics suggesting they may have regulatory functions, the researchers noted.

"This genetic association study found that ε2/ε3/ε4 alleles as well as other variants in the APOE region were associated with AD risk," Yu and his colleagues wrote. "Although future work in independent data [is] needed to replicate these results, our findings appear to provide valuable new candidate sites for targeted genetic analyses on larger sample sets representing diverse ethnic groups."

The Scan

Call for a Different Tack

Experts weigh the value of recent experiments testing genetically modified pig kidneys using brain-dead individuals, according to Nature News.

Wastewater Warning

The New York Times reports that wastewater surveillance in some parts of the US point to a possible surge.

Can't Get in the Program

Due to the Northern Ireland protocol dispute, the European Union is preventing UK researchers from joining the Horizon Europe research program, the Times of London reports.

Science Paper on Spatial-Controlled Genome Editing

In Science this week: approach to enable a CRISPR-Cas13a-based system to be used as a cancer therapy.